The objective of this research is to develop prodrugs that can be specifically converted into highly cytotoxic anticancer drugs by designed catalytic antibodies. Two aspects of the research are going to be carried out simultaneously: one involves the design and synthesis of the prodrugs and related compounds; the other involves the design and generation of catalytic antibodies that can specifically activate the designed prodrugs. Two classes of prodrugs will be designed and synthesized: 1) highly toxic drugs, which mainly include nitrogen and sulfur mustards, will be converted into nontoxic prodrugs that are resistant to natural enzymes by forming highly hindered esters and by converting the amino or sulfide moieties into ammonium or sulfonium ions; 2) highly toxic drugs, which include the mustards and other anticancer drugs, will be converted into their enol ether derivatives. Enol ethers are resistant to natural enzymes and are stable under physiological conditions. The toxicities of the mustard molecules will be eliminated by converting the nucleophilic nitrogen or sulfur atoms into positively charged ammonium and sulfonium ions. The prodrugs are designed in such ways that when they are cleaved, they will either directly release the free drugs or they will undergo a facile decomposition to yield the free drug. Catalytic antibodies that can specifically cleave (activate) the prodrugs will be developed by designing hapten molecules that contain the structural features of the prodrug molecules and at the same time, mimic the transition states for the hydrolysis of the prodrugs. These hapten molecules have been designed and are being synthesized. The haptens will be coupled to carrier protein molecules. The conjugates will be used to generate monoclonal antibodies according to standard methods. The monoclonal antibodies generated will be screened for their activities to cleave the prodrugs. Active antibodies will be used to release the toxic drugs from the corresponding prodrugs in in vitro and in vivo tests. The proposed prodrug designs represent new approaches that have not been seen so far. On the other hand, the methods for the design and generation of catalytic antibodies have been well established and will insure the activation methods as proposed here to be feasible. Physiologically stable, nontoxic prodrugs as proposed here in combination with highly specific catalytic antibodies will solve many of the major problems of current cancer chemotherapy. The catalytic antibodies proposed here will not only provide specific catalysts for prodrug activation, but also will provide artificial enzymes that can catalyze reactions not facilitated by natural enzymes. Studies of these catalytic antibodies will lead to better understanding of enzyme reaction mechanism and will also lead to the design of efficient enzyme-like biocatalysts.